Validating Syk as a Target for AML Therapy

描述(由申请人提供)：尽管进行了大剂量的细胞毒性化疗，但只有少数急性髓系白血病(AML)患者将被治愈。另一种治疗策略是诱导白血病细胞分化，这种方法已经成功地整合到使用药物全反式维甲酸治疗AML亚型急性早幼粒细胞白血病患者中。我们专注于发现通过应用化学基因组学方法来诱导AML分化的新方法。我们鉴定和验证了胞浆蛋白激酶脾酪氨酸激酶(SYK)是AML的一个新靶点，并鉴定了SYK的上游激活因子(即整合素β3)和下游效应因子(PI3K和MAPK)，并发现了与AML中最常见的突变基因之一Flt3的新的致癌伙伴关系。在这项提案中，我们期望勾勒出急性髓细胞白血病中SYK和Flt3之间致癌基因合作的关键机制基础，并确定AML中SYK和KIT之间的新的致癌伙伴关系。我们还将进行必要的临床前研究，以测试SYK抑制剂作为单一药物和高效药物组合，用于AML中PDGFR家族成员基因(Flt3和Kit)突变的患者。我们将我们的研究归结为以下几个具体目标：目的1.SYK抑制Flt3突变的AML是否具有治疗益处？目的2.急性髓系白血病中SYK和Flt3的协同作用机制是什么？目的3.SYK是否是其他PDGFR家族成员的重要调节因子？在目标1中，我们将检验Flt3突变的AML对Flt3抑制剂高度敏感的假设。我们将使用细胞系模型、原发AML患者样本以及Flt3-ITD和高度激活的SYK的骨髓移植模型，在体外和体内测试SYK导向的shRNA和SYK小分子抑制剂单独和联合抑制Flt3的活性。在目标2中，我们将确定在Flt3-ITD阳性AML中SYK被高度激活的机制，并验证SYK/Flt3白血病伙伴关系相对于MYC转录程序激活的假设。最后，在目标3中，我们将验证SYK调节AML中的PDGFR家族成员激酶试剂盒并与之合作的假设。这些研究有望为预后最差的AML患者之一--FLT3-ITD患者确定和验证新的治疗方法，并可能为携带其他PDFR家族成员激酶突变的髓系恶性肿瘤患者确定和验证新的治疗方法。我们的研究将指导未来在急性髓细胞白血病患者中测试SYK抑制剂的临床试验。

DESCRIPTION (provided by applicant): Only a minority of patients with acute myeloid leukemia (AML) will be cured of the disease despite high-dose, cytotoxic chemotherapy. An alternative therapeutic strategy is to induce differentiation of the leukemia cells, an approach that has been integrated successfully into the treatment of patients with the AML subtype acute promyelocytic leukemia by using the drug all-trans-retinoic acid. We have focused on the discovery of new approaches to induce AML differentiation by deploying a chemical genomics approach. We identified and validated the cytoplasmic kinase spleen tyrosine kinase (SYK) as a new target in AML and have characterized upstream activators (i.e., Integrin ¿3) and downstream effectors (PI3K and MAPK) of SYK in AML and discovered a new oncogenic partnership with FLT3, one of the most frequently mutated genes in AML. In this proposal, we expect to delineate the critical mechanistic underpinnings of the oncogenic cooperation between SYK and FLT3 in AML and to identify a new oncogenic partnership between SYK and KIT in AML. We will also perform the essential preclinical studies toward the testing of a SYK inhibitor as a single agent, and in highly efficacious drug combinations, for patients with mutations in the PDGFR family member genes (FLT3 and KIT) in AML. We have organized our studies into the following Specific Aims: Aim 1. Is SYK inhibition of therapeutic benefit in FLT3-mutated AML? Aim 2. What are the mechanisms of SYK and FLT3 cooperativity in AML? Aim 3. Is SYK a critical regulator of other PDGFR family member kinases? In Aim 1 we will test the hypothesis that FLT3-mutated AML will be highly sensitive to FLT3 inhibitors. We will test the activity of SYK-directed shRNA and SYK small-molecule inhibitors, alone and in combination with FLT3 inhibition, in this patient population in vitro and in vivo, using cell line models, primary patien AML samples, and a bone marrow transplantation model of FLT3-ITD and highly activated SYK. In Aim 2, we will determine the mechanism by which SYK is highly activated in FLT3-ITD-positive AML and test the hypothesis that the SYK/FLT3 leukemogenic partnership is vis-¿-vis activation of a MYC transcriptional program. Finally, in Aim 3, we will test the hypothesis that SYK regulates and cooperates with the PDGFR family member kinase KIT in AML. These studies are expected to identify and validate new therapeutic approaches for one of the worst prognosis groups of patients with AML, those with FLT3-ITD, and possibly for patients with myeloid malignancies harboring other PDFR family member kinase mutations. Our studies will guide future clinical trials testing SYK inhibitors in patients with AML.